Introduction to AVP-786
AVP-786, a drug candidate developed by Avanir Pharmaceuticals in collaboration with Concert Pharmaceuticals, was designed to treat agitation associated with dementia due to Alzheimer's disease. This compound is a deuterium-modified form of dextromethorphan, combined with quinidine sulfate, aiming to improve pharmacokinetic properties without altering its mechanism of action[1][4].
Development History
Early Clinical Trials
The clinical development of AVP-786 began in October 2012 with a Phase 1 trial involving 48 young, healthy volunteers to test the safety, tolerability, and pharmacokinetics of deuterated dextromethorphan. Subsequent Phase 1 trials were conducted in 2013 and early 2015, including comparisons with its predecessor AVP-923 and interactions with other medications[1].
Phase 3 Trials and FDA Fast-Track Designation
In November 2015, the FDA granted AVP-786 fast-track designation for the treatment of agitation associated with Alzheimer's disease. However, the TRIAD-2 study in 2019 reported negative results, showing no improvement in agitation compared to placebo. Despite this, Avanir continued with additional Phase 3 trials initiated in 2020, involving 750 participants each, to further evaluate the drug's efficacy[1][3].
Recent Developments and Termination
Phase 3 Topline Results
In February 2024, Otsuka Pharmaceutical Co., Ltd. announced the topline results of the Phase 3 trial (Trial 17-AVP-786-305; NCT03393520), which failed to show a statistically significant difference between AVP-786 and placebo in the primary efficacy endpoint, the mean change from baseline to week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total score. Adverse events included falls, urinary tract infections, and somnolence, but no deaths were attributed to AVP-786[3][5].
Termination of Development
Following the disappointing results, Otsuka decided to terminate the development of AVP-786 for the treatment of agitation associated with dementia due to Alzheimer's disease. This decision was made after a detailed analysis of the trial results, despite initial plans to continue further analyses and potential submissions for scientific publication[5].
Market Implications
Current Market Landscape
The global Alzheimer's disease treatment market is projected to grow significantly from 2024 to 2031, driven by the increasing prevalence of Alzheimer's disease and the need for effective treatments. However, the termination of AVP-786 development removes a potential contender from this market[2].
Impact on Alzheimer's Treatment Market
The failure of AVP-786 to demonstrate efficacy in treating agitation associated with Alzheimer's disease highlights the challenges in developing effective treatments for this condition. Agitation is a common and debilitating symptom affecting approximately half of all patients with Alzheimer's dementia, significantly impacting the quality of life for patients, family members, and caregivers. The absence of AVP-786 from the market means that other treatments will need to fill this gap, potentially increasing the demand for existing or emerging therapies[3].
Future Directions
Alternative Treatments
Given the unmet need for effective treatments for agitation in Alzheimer's disease, pharmaceutical companies are likely to continue investing in research and development of new therapies. The recent approval of other drugs for this patient population, as mentioned by Otsuka, indicates ongoing innovation in this area[3].
Lessons Learned
The development and termination of AVP-786 provide valuable insights into the complexities of drug development, particularly for neurological conditions. The use of deuterium chemistry, while promising in terms of pharmacokinetic improvements, did not translate into clinical efficacy in this case. This experience can inform future drug development strategies and highlight the importance of robust clinical trials[1][4].
Key Takeaways
- Development Termination: AVP-786's development was terminated due to the failure to demonstrate efficacy in Phase 3 trials.
- Market Impact: The termination affects the Alzheimer's disease treatment market, which continues to grow but lacks effective treatments for agitation.
- Future Directions: Pharmaceutical companies will continue to seek alternative treatments to address the unmet needs in Alzheimer's disease.
- Lessons Learned: The experience with AVP-786 underscores the challenges and complexities of drug development for neurological conditions.
FAQs
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What was AVP-786 intended to treat?
AVP-786 was intended to treat agitation associated with dementia due to Alzheimer's disease.
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Why was the development of AVP-786 terminated?
The development was terminated due to the failure to show a statistically significant difference between AVP-786 and placebo in the primary efficacy endpoint in Phase 3 trials.
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What is the significance of deuterium chemistry in AVP-786?
Deuterium chemistry was used to modify dextromethorphan, aiming to improve its pharmacokinetic properties without changing its mechanism of action.
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How common is agitation in Alzheimer's disease?
Agitation is reported in approximately half of all patients with Alzheimer's dementia and significantly impacts their quality of life and that of their caregivers.
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What are the implications for the Alzheimer's treatment market?
The termination of AVP-786 development means that other treatments will need to fill the gap, potentially increasing demand for existing or emerging therapies.
Sources
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AVP-786 | ALZFORUM
https://www.alzforum.org/therapeutics/avp-786
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Alzheimer's Disease Treatment Market and Forecast 2024-2031
https://www.ihealthcareanalyst.com/report/alzheimers-disease-treatment-market/
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Otsuka Announces Phase 3 Topline Results of AVP-786 in the Treatment of Agitation Associated with Dementia due to Alzheimer's Disease
https://www.otsuka.co.jp/en/company/newsreleases/2024/20240213_1.html
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Avanir Pharmaceuticals Announces Positive Interim Data From Pharmacokinetic Study With Next-Generation Compound AVP-786
https://www.prnewswire.com/news-releases/avanir-pharmaceuticals-announces-positive-interim-data-from-pharmacokinetic-study-with-next-generation-compound-avp-786-190182801.html
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Otsuka to Terminate Development of AVP-786
https://otsuka-us.com/news/otsuka-terminate-development-avp-786